1. Field of the Invention (Technical Field)
The present invention relates to metallopeptides, metal ion-complexed peptidomimetics, and metallo-constructs for the treatment of sexual dysfunction in animals, including both male erectile dysfunction and female sexual dysfunction in humans, including methods and formulations for use and administration.
2. Background Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Melanocortin Receptors. A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues. Peptides specific for melanocortin receptors have been reported to have a wide variety of biological activities.
Significant work has been done in determining the structure of melanocortin receptors, including both the nucleic acid sequences encoding for the receptors and the amino acid sequences constituting the receptors. See, for example, International Patent Applications No. PCT/US98/12098 and PCT/US99/16862 and U.S. Pat. No. 5,994,087. A large number of ligands specific for melanocortin receptors, both agonists and antagonists, have also been developed. See, for example, International Patent Applications No. PCT/US98/03298 (iodo group-containing melanocortin receptor-specific linear peptide), PCT/GB99/01388 (MC1-R specific linear peptides), PCT/GB99/01195 (MC3-R, MC4-R and MC5-R specific cyclic peptides), PCT/US99/04111 (MC1-R specific peptide antagonists for melanoma therapy), PCT/US99/09216 (isoquinoline compounds as melanocortin receptor ligands), PCT/US99/13252 (spiropiperdine derivatives as melanocortin receptor agonists), PCT/US00/14930 (substituted piperidines as melanocortin-4 receptor agonists), PCT/US00/19408 (peptide-based melanocortin receptor-3 ligands to treat sexual dysfunction), and U.S. Pat. No. 6,054,556 (cyclic lactam peptides as MC1-R, MC3-R, MC4-R and MC5-R antagonists). In addition, a large number of patents teach various methods of screening and determining melanocortin receptor-specific compounds, as for example International Patent Applications No. PCT/US97/15565, PCT/US98/12098 and PCT/US99/16862 and U.S. Pat. Nos. 5,932,779 and 5,994,087.
In general, compounds specific for MC1-R are believed to be useful for treatment of melanoma, including use as radiotherapeutic or drug delivery agent, and as diagnostic imaging agents, particularly when labeled with a diagnostic radionuclide. Compounds specific for MC3-R, MC4-R or MC5-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for treatment of obesity, for use in treatment of anorexia, as a weight gain aid, and other treatment of other food intake and metabolism-related purposes. Compounds specific for MC3-R and MC4-R are believed to be useful as agents for treatment of sexual dysfunction, including male erectile dysfunction. Compounds specific for MC3-R and MC4-R are believed to be useful to regulate blood pressure, heart rate and other neurophysiologic parameters. Other melanocortin receptor peptides are believed to be useful as tanning agents, to increase melanin production, such as peptides that are MC1-R agonists. Compounds specific for MC1-R and MC3-R may be useful in regulation of inflammatory processes.
Sexual Dysfunction and Melanocortin Receptors. Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, are common medical problems. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.
At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra®, a brand of sildenafil, which is a phosphodiesterase 5 inhibitor, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E1, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.
A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the United States Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.
Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments. Melanotan-II is a peptide of the formula Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-NH2. Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555, and commonly owned pending application PCT/US00/18217, entitled Compositions And Methods For Treatment Of Sexual Dysfunction, filed Jun. 29, 2000. The application PCT/US00/18217 discloses a peptide of the formula Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH which may be administered by a variety of routes, including nasal administration. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins.
In use of Melanotan-II, significant erectile responses were observed, with 8 of 10 treated men developing clinically apparent erections, and with a mean duration of tip rigidity greater than 80% for 38 minutes with Melanotan-II compared to 3.0 minutes with a placebo. The drug was administered by subcutaneous abdominal wall injection, at doses ranging from 0.025 to 0.157 mg/kg body weight. Transient side effects were observed, including nausea, stretching and yawning, and decreased appetite.
Other peptides and constructs have been proposed as ligands that alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitled Spiropiperidine Derivatives as Melanocortin Receptor Agonists, and in International Patent Application Nos. PCT/US00/14930 and PCT/US00/19408.
In general, all natural melanocortin peptides share the same active core sequence, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1) of native α-MSH, including melanotropin neuropeptides and adrenocorticotropin. MC3-R has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of induction of erectile response has not been fully elucidated, it has been generally accepted that the response involves the central nervous system, and binding to MC3-R and/or MC4-R.
Patent Cooperation Treaty Patent Application Serial No. PCT/US00/16396, entitled Melanocortin Receptor-Specific Metallopeptide Constructs, Combinatorial Libraries and Applications, filed on Jun. 14, 2000, commonly owned with this application, teaches melanocortin-specific metallopeptides. Patent Cooperation Treaty Patent Application Serial No. PCT/US99/29743, entitled Metallopeptide Combinatorial Libraries and Applications, filed Dec. 14, 1999, U.S. Pat. No. 6,027,711, entitled Structurally Determined Metallo-Constructs and Applications, issued Feb. 22, 2000, and U.S. Pat. No. 5,891,418, entitled Peptide—Metal Ion Pharmaceutical Constructs and Applications, issued Apr. 6, 1999, all commonly owned with this application, each teach metallopeptides generally. The specifications of the foregoing applications are incorporated herein by reference.